The immune system uses many mechanisms for attacking pathogens, but not all of these are activated after immunization. Protective immunity induced by vaccination is dependent on the capacity of the vaccine to elicit the appropriate immune response to either resist, control, or eliminate the pathogen. Depending on the pathogen, this may require a cell-mediated or humoral immune response, which, in turn, is determined by the nature of the T cells that develop after immunization. For example, many bacterial, protozoal and intracellular parasitic and viral infections appear to require a strong cell-mediated immune response for protection, while other pathogens, such as helminths, primarily respond to a humoral, or antibody, response.
The current paradigm of the role of T cells in the particular immune response is that CD4.sup.+ T cells can be separated into subsets on the basis of the repertoire of cytokines produced and that the distinct cytokine profile observed in these cells determines their function. This T cell model includes two major subsets: T.sub.H 1 cells that produce IL-2 and Interferon .gamma. (IFN-.gamma.) and mediate cellular immune responses, and T.sub.H 2 cells that produce IL-4, IL-5, and IL-10 and augment humoral immune responses [T. R. Mosmann et al, J. Immunol., 126:2348 (1986)].
Many vaccine compositions employ adjuvants, that is, substances which enhance the immune response when administered together with an immunogen or antigen. Adjuvants are thought to function in several ways, including by increasing the surface area of antigen, prolonging the retention of the antigen in the body thus allowing time for the lymphoid system to have access to the antigen, slowing the release of antigen, targeting antigen to macrophages, activating macrophages, or otherwise eliciting non-specific activation of the cells of the immune system [see, e.g., H. S. Warren et al, Annu. Rev. Immunol., 4:369 (1986)]. Currently, an essential role of adjuvants in vaccines is to direct CD4.sup.+ T cell subset differentiation, although how adjuvants perform this function is poorly understood.
The ability of a adjuvant to induce and increase a specific type of immune response and the identification of that ability is thus a key factor in the selection of particular adjuvants for vaccine use against a particular pathogen. Typical adjuvants include water and oil emulsions, e.g., Freund's adjuvant, and chemical compounds such as aluminum hydroxide or alum. At present, alum is the only adjuvant approved in the United States for human vaccines; it has been determined that alum induces the production of T.sub.H 2 cells.
Many bf the most effective adjuvants include bacteria or their products, e.g., microorganisms such as the attenuated strain of Mycobacterium bovis, bacillus Calmette-Guerin (BCG); microorganism components, e.g., alum-precipitated diphtheria toxoid, bacterial lipopolysaccharide and endotoxins. However, the role that the bacteria play is ill-defined. Recently, it has been noted that many bacteria or their products, lipopolysaccharide, Staphylococcus aureus, Mycobacterium tuberculosis, and C. parvum, stimulate IL-12 production by macrophages [A. D'Andrea et al, J. Exp. Med., 176:1387 (1992)].
However, despite their immunostimulating properties, many bacterial adjuvants have toxic or other negative effects, particularly in humans. For example, such a large population has been exposed to some of the bacterial adjuvants, like BCG, that there is a danger of eliciting a secondary response with future use as a vaccine adjuvant. Heat-killed bacteria, being non-native to mammalian hosts, also risk causing toxic effects in the host. In fact, the only currently well-accepted adjuvant for human use is the compound, alum.
Thus, there exists a need in the art for additional adjuvants which are useful in stimulating or enhancing the host's immune responses without inducing a toxic effect, and which are suitable for use in pharmaceutical compositions, such as vaccines.